Over the years, numerous methods have been proposed for improving the delivery of biologically active agents, and in particular, small molecule anticancer compounds. Challenges associated with the formulation and delivery of cancer chemotherapeutics can include poor aqueous solubility, toxicity, low bioavailability, instability, and rapid in-vivo degradation, to name just a few. Although many approaches have been devised for improving the delivery of anticancer compounds, no single approach is without its significant drawbacks. For instance, commonly employed drug delivery approaches aimed at solving or at least ameliorating one or more of these problems include drug encapsulation, such as in a liposome, polymer matrix, or unimolecular micelle, covalent attachment to a water-soluble polymer such as polyethylene glycol, use of gene targeting agents, nanoparticles, and the like.
The clinical effectiveness of many small molecule therapeutics, and oncolytics in particular, is limited by several factors. For instance, irinotecan and other camptothecin derivatives undergo an undesirable hydrolysis of the E-ring lactone under alkaline conditions. Additionally, administration of irinotecan causes a number of troubling side effects, including leucopenia, neutropenia, and diarrhea. Due to its severe diarrheal side-effect, the dose of irinotecan that can be administered in its conventional, unmodified form is extremely limited, thus hampering the efficacy of this drug and others of this type. Such harsh side effects, when severe, can be sufficient to arrest further development of such drugs as promising therapeutics. Additional challenges facing small molecule oncolytics include high clearance rates and minimal tumor permeation and residence time. Indeed, many chemotherapies are often accompanied by ultimate failure. Thus, the design and development of biocompatible delivery systems for anticancer compounds, as well as related therapeutic methods continues to present a significant challenge. Such challenge is met by the compounds and methods provided herein.